PROJECT SUMMARY Identification of dietary factors that delay decline in cognitive function has important implications for reducing the burden of Alzheimer's dementia (AD) and reducing health care costs as the population ages. Inadequate intakes of vitamins D and vitamin K are common among the elderly, and both these nutrients increase risk of cognitive impairment when fed in low amounts in animal models. However, there is a fundamental gap in knowledge about the forms of vitamins D and K present in the human brain or how these individual forms are linked to AD neuropathology and biomarkers of nutrient status. In the absence of that knowledge, design of clinical trials to test therapeutic roles of vitamins D and/or K in reducing AD burden is premature. The overall goal of the proposed research is to study the associations between vitamins D and K and AD neuropathology in older persons with and without cognitive impairment from a well-characterized community-based study. Guided by strong preliminary data, this objective will be accomplished by pursuing three specific aims leveraging the Memory and Aging Project (MAP), a clinical-pathologic prospective epidemiologic cohort study: Specific Aim 1: To identify the forms and levels of vitamin D and vitamin K and their metabolites in human brain tissue collected from two neocortical regions associated with AD risk and one region unrelated to AD risk from up to 500 deceased MAP participants, and to relate these nutrient levels to markers of brain neuropathology and to cognitive decline; Specific Aim 2: To measure vitamin D and vitamin K and their metabolites in serum samples collected in a subset of 170 MAP participants over two time points to determine if these serum levels predict cognitive decline, as well as predict brain levels of vitamins D and K.; and Specific Aim 3: Determine dietary contributors, including diet patterns and individual vitamin intakes, to brain and serum vitamin D and vitamin K levels and cognitive decline in MAP participants. The proposed approach is innovative because it builds on animal models to determine whether vitamins D and K in the human brain relate to neuropathologically-defined AD. Furthermore, the proposed research will determine whether dietary intakes and serum levels of these nutrients reflect corresponding levels in the brain. A recent meta-analysis indicated that there is an immediate need for human studies, such as the one proposed here, to determine the significance of the association between biomarkers of nutrient status and AD risk. Thus the proposed research is significant because these two nutrients, which are generally consumed below recommended intakes for older persons, are modifiable, low-cost, yet safe when consumed in higher amounts. Successful completion of the proposed study will provide the first data on vitamins D and K in human brain tissue, and will provide the foundation for future studies on the impact of modifying vitamin D and/or vitamin K on AD risk.